As discussed generally by Jean Marx at page 320 of Science, Vol. 265 (Jul. 15, 1994), each year about 330,000 patients in the United States undergo coronary and/or peripheral angioplasty, a procedure designed to open up blood vessels, e.g., coronary arteries, clogged by dangerous atherosclerotic plaques (atherosclerosis) and thereby restore normal blood flow. For a majority of these patients, the operation works as intended. Nearly 33% of these patients (and maybe more by some accounts), however, develop restenosis, wherein the treated arteries become quickly clogged again. These patients are no better off, and sometimes worse off, than they were before angioplasty. Excessive proliferation of smooth muscle cells in blood vessel walls contributes to restenosis.
Improvements in the therapy, prophylaxis and diagnosis of restenosis and/or atherosclerosis, especially in compositions therefore and methods thereof, would be an advance over the state of the art.
In 1950, Patterson and Cottral, in Arch. Pathol. 1950; 49:699, called attention to the development of coronary atherosclerosis in chickens ill with Marek's lymphomatosis, the etiological agent of which was subsequently discovered to be a herpesvirus now known as Marek's Disease Virus.
Melnick et al. in European Heart Journal (1993) 14 (Supplement K), 30-38, and BioEssays Vol. 17, No. 10 pp. 899-903 (1995) report that the finding in chickens prompted studies of human herpesviruses with respect to human atherosclerosis.
In Melnick et al., European Heart Journal, supra, circumstantial evidence for involvement of CMV is presented. This evidence includes finding CMV antigen and nucleic acid sequences in arterial smooth muscle cells of humans, seroepidemiological studies showing high levels of CMV antibodies found associated with clinically manifest atherosclerotic disease, suggesting that a periodically activated latent infection or a continuously active infection is present in patients with atherosclerosis. However, the viral genome, but not the infectious virus, was found in arterial cells, leading the authors to assert that the artery itself may be the site of CMV latency. The authors caution that their observations do not demonstrate that viruses have a role in the pathogenesis of atherosclerosis.
In Melnick et al., BioEssays, supra, the authors report that antigens and nucleic acid sequences of CMV, a widespread member of the herpesvirus family, were found in arterial lesions in human atherosclerosis; but, infectious virus has not been observed. In atherosclerosis patients, high levels of CMV antibodies are present, suggesting the presence of virus that had been activated from a latent state.
There is no teaching or suggestion in Melnick et al., BioEssays, supra, of any particular CMV vaccine or any particular strategy for treatment, prevention or diagnosis of restenosis or atherosclerosis.
Speir et al., Science 265:391-394 (Jul. 15, 1994) postulate that restenosis may be triggered by activation of latent CMV, e.g., by angioplasty-induced injury to the vessel wall, that causes multiple cellular changes and predispose SMCs to proliferate. For instance, Speir et al. postulate that CMV protein IE84 combines with and inactivates p53 in smooth muscle cells, which, in turn could predispose the cells towards increased growth, analogous to the way p53 inactivation is believed to contribute to the formation of malignant tumors. This CMV-mediated inhibition of p53, assert Speir et al., may in part explain the monoclonality observed in some atherosclerotic lesions (see Benditt and Benditt, PNAS USA 70: 1753 (1973)).
As Jean Marx, supra, observed, the Speir et al. hypothesis is just one of many potential mechanisms by which the virus may produce restenotic lesions. Jean Marx, supra, further observed that CMV activation cannot explain all cases of restenosis, as signs of a CMV-p53 interaction have not been found in about 67% of the restenosis samples.
Golubev et al., U.S. Pat. No. 5,534,258 (not admitted to be prior art), relates to four polypeptides from certain herpesviruses; specifically two polypeptides from HSV-1, and two polypeptides from CMV. Golubev et al., without any data, speculates that this shotgun approach of a combination of all four of these polypeptides, in equal proportion, is a prophylactic vaccine against pathogenic development of atherosclerotic plaque. No protection data is presented.
Literature involving CMV and/or restenosis and/or atherosclerosis, as discussed above likewise fails to teach or suggest any therapy or prophylaxis or any detection methods, or any compositions therefor, for restenosis and/or atherosclerosis, as in the present invention. Indeed, heretofore there had not been a definitive teaching or suggestion in the art of a relation between the presence of antibodies to CMV at the time of angioplasty, indicating prior exposure to CMV, and the subsequent development of restenosis. And, even if, assuming arguendo (with no admission), one asserted some sort of teaching or suggestion of any relation between CMV or antibodies thereto and restenosis and/or atherosclerosis, there is still a failure to teach or suggest any therapy or prophylaxis or any detection methods, or any compositions therefor, for restenosis and/or atherosclerosis, as in the present invention.
It would indeed be an advance in the art to show a connection between CMV and restenosis and/or atherosclerosis, especially mechanisms involving the virus, including such as the virus, by inhibiting either the capacity of p53 to block cell cycle progression, or its capacity to initiate apoptosis, enhances SMC accumulation and thereby facilitates development of restenotic lesions, as herein.
Indeed, it is believed that heretofore there has been no evidence linking viremia and angioplasty, such as balloon angioplasty, and subsequent restenosis in humans, e.g., no boost of immune response, such that there is a fortiori no teaching or suggestion of any prophylaxis or treatment for restenosis and/or atherosclerosis or compositions therefor or methods for making such compositions.